Autoimmune processes in the placentas of neural tube defect-affected pregnancies

Neural Tube Defects (NTDs) are a group of common congenital malformations that result from incomplete neural tube closure leading to abnormalities of the brain and/or spinal cord. Unfortunately, their etiology remains unknown, probably due to complex multifactorial interactions. The protective effect of dietary folates in preventing NTDs is well known, but this beneficial effect is limited to the 60 to 70% of cases; leaving 30% of the population without any known option for improving pregnancy outcomes. The mechanism by which folates rescue NTD-affected embryos is poorly understood, but the ability of folate supplementation to overcome a significant percentage of NTDs and the critical role of 5-methyltetrahydrofolate in the remethylation of homocysteine (Hcy) to methionine in the placenta suggests that folate binding and/or transport might play a critical role during development. We hypothesized that maternal autoantibodies (AB) targeting placental folate receptor alpha (FRα) are blocking the receptor and limiting the ability of the FRα to bind folates, reducing intraembryonic folate levels. Furthermore, we hypothesized that AB binding to other relevant proteins required for trophoblastic growth and placentation can be involved in activating pathologic inflammatory pathways that can result in suboptimal uptake of nutrients and contribute to an abnormal closure of the neural tube. We developed a high throughput ELISA to evaluate whether mothers experiencing pregnancies complicated with NTDs are more likely to have placental AB to FRα than are mothers experiencing normal pregnancies. We optimized and simplified a protocol for AB elution from placental tissues and determined whether these antibodies were blocking the FRα from binding with available folates. Although anti-FRα IgG antibodies were not associated to the blocking activity in this study, we found that the blocking activity was higher in the placentas from NTD-affected pregnancies compared to controls, that FRα IgM antibodies are most likely the type of antibody produced during gestation that is most relevant to the blocking activity and that it is unlikely that autoimmunity against other developmental proteins associated with NTDs is generating the NTDs.